calcium and parkinson's disease

Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA, This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, Calcium, -synuclein, Parkinson's disease, {"type":"clinical-trial","attrs":{"text":"NCT02168842","term_id":"NCT02168842"}}, {"type":"clinical-trial","attrs":{"text":"NCT00037830","term_id":"NCT00037830"}}, {"type":"clinical-trial","attrs":{"text":"NCT00329056","term_id":"NCT00329056"}}, {"type":"clinical-trial","attrs":{"text":"NCT00740714","term_id":"NCT00740714"}}, {"type":"clinical-trial","attrs":{"text":"NCT00449865","term_id":"NCT00449865"}}, {"type":"clinical-trial","attrs":{"text":"NCT01280123","term_id":"NCT01280123"}}. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Yuan H.-H., Chen R.-J., Zhu Y.-H., Peng C.-L. and Zhu X.-R. (2013). Across all kingdoms in the tree of life, calcium (Ca2+) is an essential element used by cells to respond and adapt to constantly changing environments. A. and McLean P. J. For example, the ER network is highly connected with many organelles through Ca2+-dependent pathways, including the plasma membrane, mitochondria, lysosomes and possibly other organelles (Bahar et al., 2016; Berridge et al., 2003; Bezprozvanny, 2010; Bootman, 2012; Cal et al., 2011; Carafoli, 2002; McBrayer and Nixon, 2013; Phillips and Voeltz, 2016; Rivero-Rios et al., 2014; Wojda et al., 2008). DJ1 is a ROS scavenger that protects cells from ROS-induced cell death. Rin GTPase couples nerve growth factor signaling to p38 and b-Raf/ERK pathways to promote neuronal differentiation. A comprehensive glossary of autophagy-related molecules and processes. Golgi fragmentation has been observed in cellular and animal models of PD, as well as in post-mortem brain samples from PD patients (Fujita et al., 2006; Gosavi et al., 2002; Lin et al., 2012; Rendn et al., 2013). (2003). Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Endogenous Ca2+ buffer concentration and Ca2+ microdomains in hippocampal neurons. Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression, LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. Lynch-Day M. A., Mao K., Wang K., Zhao M. and Klionsky D. J. Bethesda, MD 20894, Web Policies (2014). Reese L. C., Zhang W. R., Dineley K. T., Kayed R. and Taglialatela G. (2008). Lee C. H., Della N. G., Chew C. E. and Zack D. J. In addition, the peptide TFP5, which is derived from p35, is reported to be neuroprotective in the MPTP-treated rat cortical neurons and a mouse model of PD (Binukumar and Pant, 2016; Binukumar et al., 2015; Zhang et al., 2012). Angelova P. R., Ludtmann M. H. R., Horrocks M. H., Negoda A., Cremades N., Klenerman D., Dobson C. M., Wood N. W., Pavlov E. V., Gandhi S. et al. (2001). Zeng H., Chattarji S., Barbarosie M., Rondi-Reig L., Philpot B. D., Miyakawa T., Bear M. F. and Tonegawa S. (2001). Presenilins can modify lysosomal and ER Ca2+ channels (Kayala et al., 2012; Nelson et al., 2011) and have been implicated in familial forms of AD (Tolia and De Strooper, 2009). Striatal inhibition of calpains prevents levodopa-induced neurochemical changes and abnormal involuntary movements in the hemiparkinsonian rat model. Calbindin-D9k is mostly known for buffering Ca2+ in erythrocytes, whereas calbindin-D28k buffers Ca2+ in the central nervous system where it participates in the blockade of multiple pro-apoptotic pathways (Baimbridge et al., 1992). Abstract. Accessibility These include: RIT2 (Rin), a GTP-binding protein that is involved in DA neuronal function by regulating DAT trafficking and consequently extracellular dopamine concentrations (Table1, Fig. These data indicate that SOCE is important for maintaining the appropriate levels of dopamine in a normal brain and that alterations in this pathway might lead to PD-like pathology. Three other proteins associated with autosomal-dominant forms of PD affect Ca2+ homeostasis both in the lysosome and in endosomal compartments. Ramonet D., Podhajska A., Stafa K., Sonnay S., Trancikova A., Tsika E., Pletnikova O., Troncoso J. C., Glauser L. and Moore D. J. Pathak T., Agrawal T., Richhariya S., Sadaf S. and Hasan G. (2015). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Parkinson's disease is associated with altered expression of CaV1 channels and calcium-binding proteins. These interactions promote MAM assembly and function by controlling ER-mitochondria Ca2+ and lipid homeostasis (Table1, Fig. Kikuchi A., Takeda A., Kimpara T., Nakagawa M., Kawashima R., Sugiura M., Kinomura S., Fukuda H., Chida K., Okita N. et al. Phosphorylation of microtubule-associated protein tau by Ca2+/calmodulin-dependent protein kinase II in its tubulin binding sites, Disassembly of microtubules by the action of calmodulin-dependent protein kinase (Kinase II) which occurs only in the brain tissues, Calmodulin-dependent protein kinase (kinase II) which is involved in the activation of tryptophan 5-monooxygenase catalyzes phosphorylation of tubulin. Cdk5/p25(nck5a) interaction with synaptic proteins in bovine brain. PD can increase your risk of falling. (2009). Vesicles, another type of acidic organelle, are also highly affected in PD. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Pasternak B., Svanstrom H., Nielsen N. M., Fugger L., Melbye M. and Hviid A. Parkinson's disease is a condition that affects the nervous system. Gmez-Snchez R., Gegg M. E., Bravo-San Pedro J. M., Niso-Santano M., Alvarez-Erviti L., Pizarro-Estrella E., Gutirrez-Martn Y., Alvarez-Barrientos A., Fuentes J. M., Gonzlez-Polo R. A. et al. The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity, Role of mitochondrial Ca2+ in the regulation of cellular energetics. BST1 is an adenosine diphosphate ribose (ADP) cyclase that can regulate Ca2+ release from the ER through the ryanodine receptors (RyR) by generation of cyclic ADP ribose (cADPR), a potent and universal Ca2+ mobilizer (Bruzzone et al., 2003; Nayak and De, 2007). Unlike Na+ and K+, which have 10- to 30-fold differences in ion concentration across the plasma membrane, Ca2+ ions have a 20,000-fold lower concentration in the cytoplasm compared to in the extracellular space (Surmeier and Schumacker, 2013). McKee A. C., Kosik K. S., Kennedy M. B. and Kowall N. W. (1990). Olson P. A., Tkatch T., Hernandez-Lopez S., Ulrich S., Ilijic E., Mugnaini E., Zhang H., Bezprozvanny I. and Surmeier D. J. (2012). The extracellular fragment of GPNMB (Glycoprotein nonmelanosoma protein B, osteoactivin) improves memory and increases hippocampal GluA1 levels in mice. (2014). Calcium, Bioenergetics, and Parkinson's Disease Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson's disease (PD). GM1 ganglioside in Parkinson's disease: results of a five year open study. Additional evidence also suggests a pathological role for -synuclein in the increased influx of Ca2+ through the plasma membrane in PD. GM1 is also neuroprotective in rodent models of PD (Figs1 and and2)2) (Schneider, 1998). sharing sensitive information, make sure youre on a federal (2005). Your daily values may be higher or lower depending on your calorie needs. Fluegge D., Moeller L. M., Cichy A., Gorin M., Weth A., Veitinger S., Cainarca S., Lohmer S., Corazza S., Neuhaus E. M. et al. Michael D. J., Cai H., Xiong W., Ouyang J. and Chow R. H. (2006). Given that the exact roles of Cav1.2 channels in PD have not been fully elucidated, this should be an important consideration when interpreting the results of these clinical trials. Abbreviations: BST1, bone marrow stromal cell antigen-1; Complex 1, NADH coenzyme Q oxidoreductase; DJ1, protein deglycase; ER, endoplasmic reticulum; GM1, monosialotetrahexosylganglioside; Grp75, glucose-regulated protein 75; H+, hydrogen ion (protons); IP3R, inositol trisphosphate receptor; LRRK2, leucine-rich repeat kinase 2; MCU, mitochondrial Ca2+ uniporter; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NAD+, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; Parkin, ligase encoded by the PRKN (PARK2) gene; PD, Parkinsons disease; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species; RyR, Ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; VDAC, voltage-dependent anion channel type 1. Smith P. D., Mount M. P., Shree R., Callaghan S., Slack R. S., Anisman H., Vincent I., Wang X., Mao Z. and Park D. S. (2006). Smani T., Zakharov S. I., Csutora P., Leno E., Trepakova E. S. and Bolotina V. M. (2004). Mishima T., Fujiwara T., Sanada M., Kofuji T., Kanai-Azuma M. and Akagawa K. (2014). (2011). FOIA We would like to thank Niccolo E. Mencacci and Steven J. Lubbe for helpful discussions. Mutations in SYNJ1 that affect its phosphatase function are associated with early-onset progressive parkinsonism with generalized seizures (EOP) (Krebs et al., 2013; Lee et al., 2004). Clinical overview of the synucleinopathies. (2016). Stages in the development of Parkinson's disease-related pathology. alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. Lees A. J., Hardy J. and Revesz T. (2009). Sakamoto K., Karelina K. and Obrietan K. (2011). A total of 64 adult male Spraque-Dawley rats were divided The electrical activity of neurons and other excitable cells relies on several different types of voltage- and ligand-gated ion channels that are permeable to inorganic ions, such as Na+, K+, Cl and Ca2+. Exner N., Lutz A. K., Haass C. and Winklhofer K. F. (2012). Dreses-Werringloer U., Lambert J.-C., Vingtdeux V., Zhao H., Vais H., Siebert A., Jain A., Koppel J., Rovelet-Lecrux A., Hannequin D. et al. Calcium/phospholipid-dependent protein kinase (protein kinase C) phosphorylates and activates tyrosine hydroxylase, A novel haplotype-sharing approach for genome-wide case-control association studies implicates the calpastatin gene in Parkinson's disease, SNPs in CAST are associated with Parkinson disease: a confirmation study. Muller A., Kukley M., Stausberg P., Beck H., Muller W. and Dietrich D. (2005). Human RME-8 is involved in membrane trafficking through early endosomes. Dragicevic E., Poetschke C., Duda J., Schlaudraff F., Lammel S., Schiemann J., Fauler M., Hetzel A., Watanabe M., Lujan R. et al. Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Parkinson's disease-associated proteins and their connection to Ca2+ homeostasis. EIF2AK3 is a risk gene associated with progressive supranuclear palsy (PSP) (Hglinger et al., 2011). A. Vitamin C 0% Iron 6% CREB: a multifaceted regulator of neuronal plasticity and protection. (2006). Kayala K. M. N., Dickinson G. D., Minassian A., Walls K. C., Green K. N. and LaFerla F. M. (2012). A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. A novel CaM kinase II pathway controls the location of neuropeptide release from Caenorhabditis elegans motor neurons. Wang W., Wang X., Fujioka H., Hoppel C., Whone A. L., Caldwell M. A., Cullen P. J., Liu J. and Zhu X. Damier P., Hirsch E. C., Agid Y. and Graybiel A. M. (1999). As such, understanding the mechanisms by which Ca2+ signaling contributes to the progression of PD is vitally important for developing effective therapies to treat this disease. Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Calcium (Ca(2+)) is an almost universal second messenger that regulates important activities of all eukaryotic cells. In MSA and DLB, Lewy bodies are primarily found in oligodendrocytes and cortical neurons, respectively. Excess levels of either calcium or alpha-synuclein . (2012). Calcium and vitamin D Osteoporosis is a condition that affects the bones, causing them to become weak and fragile and more likely to break. A total of 28 idiopathic PD patients were subjected to motor symptoms evaluation using the modified Hoehn-Yahr . Excessive levels of calcium in the brain may trigger the formation of toxic protein clumps that typify Parkinson's disease. Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum, Calmodulin: a prototypical calcium sensor. Sidransky E., Nalls M. A., Aasly J. O., Aharon-Peretz J., Annesi G., Barbosa E. R., Bar-Shira A., Berg D., Bras J., Brice A. et al. B., Fine N., Pullen T. J., Cane M. C., Hu M., Chabosseau P., Meur G., Velayos-Baeza A., Monaco A. P., Marselli L. et al. ER-Mitochondria contact sites: a new regulator of cellular calcium flux comes into play. National Library of Medicine Guzman J. N., Sanchez-Padilla J., Wokosin D., Kondapalli J., Ilijic E., Schumacker P. T. and Surmeier D. J. Mouatt-Prigent A., Karlsson J.-O., Yelnik J., Agid Y. and Hirsch E. C. (2000). Parkinson's disease (PD) is a progressive neurodegenerative disease characterized typically by motor features of tremor, rigidity and bradykinesia, due to depletion of dopaminergic nigrostriatal neurons. Saad M., Lesage S., Saint-Pierre A., Corvol J.-C., Zelenika D., Lambert J.-C., Vidailhet M., Mellick G. D., Lohmann E., Durif F. et al. Bootman M. D., Lipp P. and Berridge M. J. (2010). Calcium signaling: a tale for all seasons. This suggests that Ca2+ could be a key player in coordinating complex organelle networks to ultimately achieve metabolic interactions, intracellular signaling, cellular maintenance and regulation of cell survival. Di Fonzo A., Dekker M. C. J., Montagna P., Baruzzi A., Yonova E. H., Correia Guedes L., Szczerbinska A., Zhao T., Dubbel-Hulsman L. O. M., Wouters C. H. et al. Altered PA levels are likely to contribute to the altered cortical excitability and oscillatory activity previously documented in PD (Lanoue et al., 2013). A. T., Honigmann A., Jahn R. and van den Bogaart G. (2016). L-type (also known as Cav1 family) voltage-gated Ca2+ channels, Cav1.2 and Cav1.3, have been implicated in PD (Cal et al., 2014; Hurley and Dexter, 2012; Ortner and Striessnig, 2016; Schapira, 2013; Surmeier et al., 2016; Zamponi, 2016). The organisation and functions of local Ca(2+) signals, Mitochondrial dysfunction in Parkinson's disease. Several epidemiological studies suggest that there is indeed a reduced risk of developing PD in patients with long-term use of Isradipine (Becker et al., 2008; Lee et al., 2014; Pasternak et al., 2012; Ritz et al., 2010). Ca2+ is pumped out of mitochondria via Ca2+ exchange channels, such as the mitochondrial Na+/Ca2+ exchanger (mNCX), which is regulated by PINK1. government site. In support of a role for SOCE in the normal physiology of DA neurons in the SNc, overexpression of a dominant-negative form of the SOCE channel in the Drosophila brain, Orai1 (see Fig. p25 and overactive Cdk5 are detected in PD animal models (Qu et al., 2007; Smith et al., 2003) and in Lewy bodies from postmortem PD brains (Alvira et al., 2008; Takahashi et al., 2000). Rendn W. O., Martnez-Alonso E., Toms M., Martnez-Martnez N. and Martnez-Menrguez J. Binding of CaM to -synuclein accelerates -synuclein fibril formation in vitro, potentially contributing to PD pathogenesis (Lee et al., 2002; Martinez et al., 2003). Although it is now increasingly recognized that gradual Ca2+ dysregulation might be a key contributor for aging, what distinguishes its contribution to PD from that to normal aging and/or other neurological diseases is that many of the genes that give rise to PD have a known causal role in Ca2+ homeostasis. Chen Y. P., Song W., Huang R., Chen K., Zhao B., Li J., Yang Y. and Shang H.-F. (2013). Palop J. J., Jones B., Kekonius L., Chin J., Yu G.-Q., Raber J., Masliah E. and Mucke L. (2003). Nishi A., Bibb J. Moreover, -synuclein and DJ-1 have both been shown to interact with MAM via the chaperone Grp75 (Jin et al., 2007). The role of Golgi as Ca2+ reservoirs in PD pathology remains unclear at present. Although the presynaptic role of CaMKII in PD is not fully understood, it has a role in both the initiation and prevention of dopamine release (Hoover et al., 2014; Michael et al., 2006; Wang, 2008). Parkinson's disease (PD) is a common neurodegenerative disorder of which the core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). InsP3-mediated intracellular calcium signalling is altered by expression of synaptojanin-1, Calpain-mediated proteolysis of microtubule-associated protein 2 (MAP-2) is inhibited by phosphorylation by cAMP-dependent protein kinase, but not by Ca2+/calmodulin-dependent protein kinase II. In these experiments, Isradipine confers strong protection in SNc DA neurons, indicating that Ca2+ flux through L-type channels is an important contributor to neuronal cell death. An additional link between ER Ca2+ homeostasis and PD is provided by phospholipase A2G6 (PLA2G6). Wang R., McGrath B. C., Kopp R. F., Roe M. W., Tang X., Chen G. and Cavener D. R. (2013b). . (2013). Together they form a unique fingerprint. Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson's disease. Importantly, reducing cytosolic Ca2+ significantly decreases cytosolic dopamine and prevents toxicity in DA neurons in the rat SNc (Mosharov et al., 2009). Chan E. Y., Tang T., Tu H., Maximov A., Wang Z., Wellington C. L., Hayden M. R. and Bezprozvanny I. WNK4 regulates the secretory pathway via which TRPV5 is targeted to the plasma membrane. Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. (2013). The international team, led by the University of Cambridge, found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson's disease. Becker C., Jick S. S. and Meier C. R. (2008). Goldberg J. Hwang O., Choi H. J. and Park S. Y. Time is an issue when phenotypes are age dependent, as is the case for PD, and when the lifespan of rodents and/or primates is years. (2011). Another interesting Ca2+-dependent group of enzymes implicated in PD are calpains. Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease. This finding could be a new treatment target for researchers working to understand how and why people develop the neurodegenerative disease. Calcium signalling: dynamics, homeostasis and remodelling, Calcium signaling and neurodegenerative diseases, TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson's disease. Cal T., Ottolini D. and Brini M. (2014). Gmez-Suaga P., Churchill G. C., Patel S. and Hilfiker S. (2012). Puopolo M., Raviola E. and Bean B. P. (2007). Drion G., Massotte L., Sepulchre R. and Seutin V. (2011). Objective/Rationale: Parkinson's disease is associated with changes in the electrical activity of nerve cells in the basal ganglia and thalamus, including the emergence of abnormal burst discharges, due in part to dysfunction of a specific type of ion channel on nerve cell membranes, called T-type calcium channel. Elucidating the role of -synuclein, and of other PD-associated proteins, in Ca2+ homeostasis could provide new opportunities for developing novel therapeutics to treat synucleinopathies. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Kieburtz K., Tilley B. C., Elm J. J., Babcock D., Hauser R., Ross G. W., Augustine A. H., Augustine E. U., Aminoff M. J., Bodis-Wollner I. G. et al. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism. PLA2G6 loss of function impairs SOCE, thereby decreasing the appropriate refilling of the ER with Ca2+. The neuroprotective effect of overexpression of calbindin-D(28k) in an animal model of Parkinson's disease, Targeting voltage-gated calcium channels in neurological and psychiatric diseases. In support of the role of PERK in the pathology of PD, phosphorylated PERK is found in SNc DA neurons from deceased PD patients, as well as in Lewy bodies (Hoozemans et al., 2007). Mitochondria can temporally and spatially regulate cytosolic Ca2+ concentrations in distinct locations in a neuron. (2008). (2014). EIF2AK3, also known as protein kinase RNA-like endoplasmic reticulum kinase (PERK), couples ER stress to translation inhibition during protein misfolding (Table1, Fig. (2010). Ghanbari M., Darweesh S. K. L., de Looper H. W. J., van Luijn M. M., Hofman A., Ikram M. A., Franco O. H., Erkeland S. J. and Dehghan A. Up-regulation of GTP cyclohydrolase I and tetrahydrobiopterin by calcium influx. (2007). MPTP - Wikipedia MPTP MPTP ( 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a chemical precursor to the neurotoxin MPP +, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. Lysosome-derived Ca2+ is thought to trigger Ca2+ release from the ER, possibly via lysosome-ER membrane contact sites (Kilpatrick et al., 2013; Phillips and Voeltz, 2016). Kretsinger R. H. and Nockolds C. E. (1973). Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis. Marambaud P., Dreses-Werringloer U. and Vingtdeux V. (2009). 1) (Follett et al., 2013; Nath et al., 2011). In adult mice, SNc DA neurons have an increased reliance on Cav1.3 channels, as well as a decreased ability to deal with high Ca2+ levels (Chan et al., 2007; Hurley et al., 2013). CaMKII also phosphorylates TH, the rate-limiting enzyme in the biosynthesis of catecholamines, such as dopamine, noradrenaline and adrenaline, and increases dopamine synthesis (Fitzpatrick, 1999; Albert et al., 1984; Lehmann et al., 2006). Background: It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. (2003). (2003). Interestingly, a defect in lysosomal trafficking caused by a PD-associated GBA mutation (L444P) was rescued in Gaucher patient-derived fibroblasts following treatment with the L-type Ca2+ channel blockers diltiazem or verapamil (Mu et al., 2008).
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